Dormant tumor cells are known to possess characteristics of CSCs

Dormant tumor cells are known to possess characteristics of CSCs. tyrosine kinase inhibitor lapatinib along with capecitabine or other Salvianolic acid C combinations of chemotherapy and anti-HER2 therapy.3 Other potential therapeutics Cyclin dependent kinase inhibitors Cell cycle dysregulation is one of the most Rabbit Polyclonal to GSDMC important hallmarks of cancer. Cyclin dependent kinase 4/6 (CDK 4/6) inhibitors are currently being investigated extensively. The CDK 4/6 acts by forming a complex with Cyclin D1 and phosphorylating retinoblastoma protein (Rb). The phosphorylation results in inactivation of Rb and allows cells to transition from the G1 phase into S phase of the cell cycle. The inhibitors act by preventing the interaction between Cyclin D1 and CDK 4/6, and thus blocking the entry from the G1 phase into S phase. Recently, Salvianolic acid C the FDA approved the use of CDK 4/6 inhibitor palbociclib in combination with letrozole for the treatment of postmenopausal women suffering from ER+/HER2-advanced metastatic breast cancer. Other CDK 4/6 inhibitors that have been developed are abemaciclib and LEE01. In the HER2 setting, palbociclib, either alone, or in combination with trastuzumab showed growth inhibitory effects on HER2+ cell lines. Currently, a phase II clinical trial Salvianolic acid C has been undertaken to assess the safety and efficacy of palbociclib and trastuzumab, with or without letrozole, in post-menopausal patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who have received prior chemotherapy and trastuzumab for their metastatic disease.7 Immune checkpoint inhibitors Tumor antigens are recognized by T lymphocytes, which mediate an immune response against cancer cells. During this attack by T and other immune cells, the immune system enhances the activation of certain molecules known as checkpoints. Checkpoints prevent the immune reaction from damaging normal tissues in the body. Cancer cells are known to upregulate the expression of immune checkpoint molecules in order to escape the attack of the immune system. Such checkpoint molecules include cytotoxic T lymphocyteCassociated protein-4 (CTLA-4) and a co-inhibitory receptor called Programmed death 1 (PD-1), which is overexpressed on tumor-infiltrating lymphocytes (TILs). PD-L1 is the ligand for PD-1 and is overexpressed in various forms of cancer, including breast cancer. PD-1 expressing TILs are associated with poor overall survival in HER2+ breast cancer. Moreover, a positive correlation is observed between the expression of PD-L1 and anti PD-1 therapy. PD-1 inhibitors have shown promising results during the initial evaluation in triple negative breast cancer. Furthermore, Anti-PD1 antibodies showed encouraging results in HER2+ breast cancer during the preclinical studies, as synergistic effects were observed with Salvianolic acid C the combination of trastuzumab and anti-PD1 antibodies. Currently, a phase II clinical trial is being undertaken to assess the efficacy of using anti-PD-1 Salvianolic acid C monoclonal antibody and trastuzumab in patients with trastuzumab-resistant, HER2-positive metastatic breast cancers.8 Recent work by Mller et?al demonstrates that T-DM1 promotes the immune system. Despite primary resistance to immunotherapy, the combination of T-DM1 with anti CTLA-4 and anti PD-1 inhibitors renders HER2+ breast cancer susceptible to immune attack.9 Combining chemotherapy with immunotherapy would be an exciting strategy that needs to be thoroughly investigated. Drug resistance and cancer stem cell hypothesis Despite improved prognosis of the HER2 subtype of breast cancer due to the availability of targeted agents, drug resistance and tumor recurrence still remains a major concern. A fraction of patients are intrinsically resistant to drug treatment (drug resistance) whereas others acquire drug resistance over the course of treatment (acquired drug resistance). Reports indicate that breast cancer recurrence might occur up to 25 years after the treatment of primary tumor.10 Possible mechanisms for trastuzumab resistance include C overexpression of other HER family receptors, Insulin-like growth factor 1 receptor (IGF1R) upregulation, increased expression and activity of c-Met (mesenchymal-epithelial transition factor) receptor, overexpression of EphA2 receptor, overexpression of PDK1, increased activation of PI3K signaling pathway, increased Src activity, loss of tumor suppressor phosphatase and tensin homolog (PTEN), loss of p27kip1, increased expression of membrane associated glycoprotein MUC4, HER2 mutation(s) that alters the binding of trastuzumab to HER2, expression of amino-terminus truncated form of HER2-p95HER2 which sterically hinders the binding of HER2 and trastuzumab, expression of a splice variant that removes exon 16 in the extracellular domain of HER2 and rare incidence of antibody development against trastuzumab. Moreover, the inability of the host immune system to exhibit an antibody-dependent cell-mediated cytotoxicity (ADCC) response could contribute to resistance.11, 12, 13 Lapatinib resistance.